Basic esters of monoalkyl isobutyl acetic acids



Patented Mar. 11, 1947 BASIC ESTERS F MONOALKYL ISOBUTYL ACETIG ACIDSHenry Martin and Alfred Margot, Basel, Switzerand, assignors to Basel,Switzerland No Drawing. Applicati No. 549,122. In Swi 6 Claims. 1

According to experiments made by Fromherz and other authors (cf. Arch.exp. Path. u. Pharm. 173, 124 (1933)) basic esters of aliphaticcarboxylic acids do not possess manifest antispasmodic properties.Moreover, aliphatic carboxylic acid esters which have become known inthe patent literature, such as the isovaleric acid ester,a-bromoisovaleric acid ester, isopropylallyl acetic acid ester ordiethyl acetic acid ester of 3 diethylamino 2:2 dimethyl 1 propanol showalso a very slight neurotropic-atropine-like behaviour. The estersmentioned by Halpern (cf. Arch. internat. de Pharmacodyn. 59, 149(1938)), such as the ethylbutylacetic acid ester or dibutyl acetic acidester of diethylaminoethanol, the dibutyl acetic acid ester ofdiethylamino-( 1)-propanel-(3), the acetic acid ester, propionic acidester, n-butyric acid ester, diethyl acetic acid ester, ethylbutylaceticacid ester or the dibutyl acetic acid ester ofdiethylamino-(1)-pentanol- (4) are not substantially more efiicacious.

In contradistinction thereto it has surprisingly been found that basicesters of the monoallgyl isobutyl acetic acids possess excellentantispas modic properties. Such a behaviour could, of course, neither beforeseen nor expected.

For the preparation of the esters for instance reactive derivatives ofthe monoalkyl isobutyl acetic acids, i. e. their halides, esters oranhydrides, are caused to react in the presence or absence ofcondensation agents with amino alcohols which are tertiarily substitutedat the nitrogen atom; another method consists in causing reactive estersof the said amino alcohols to react, if necessary in the presence ofacid binding agents, with the above cited acids or their saltsrespectively.

By the expression reactive esters of amino alcohols especially esterswith hydrogen halide acids, with aryl sulfonic acids and the like may beunderstood.

Furthermore, it is also possible to convert monoalkyl isobutyl aceticacids into their halogen alkyl esters and to cause the latter to reactwith secondary amines. For the preparation of the halogen alkyl estersit is advantageous to cause alkylene halogen hydrines to react withmonoalkyl isobutyl acetic acids or halides, esters or anhydridesrespectively in the presence or absence of condensation agents or toallow alkylene halogen hydrines or alkylene dihalides to react withsalts of the said acids and finally to replace the hydroxyl groups whichmay be present in the resulting compounds by halogen.

The basic esters claimed herein are soluble in the firm J. R. Geigy A.G.,

on August 11, 1944, Serial tzerland August 4, 1943 Example 1 9 parts ofn-propyl isobutyl acetic acid chloride or corresponding quantities ofthe bromide are added under stirring to 6 parts of diethylamincethanoland the resulting mixture is heated, while further stirring, for a shorttime to 160 0., whereby under development of heat a bright brown oil isobtained which advantageously is treated with water while warm. Theaqueous solution is extracted several times with ether and the baseisthen freed by means of concentrated ammonia. The base is extractedwith ether and, after Washing with water and drying the etherealsolution, the solvent is distilled off. The residue boils at 16 mm.pressure at -147 C.

In an analogous manner the esters can also be produced with other basicalcohols, such as dimethylaminoethanol (B. P. 11'7-120 C. at 12 mm.pressure), dimethylaminopropanol (B. P. 130-132 C. at 11 mm. pressure),diethylaminopropanol (B. P. 148-l50 C. at 11 mm. pressure),piperidinoethanol (B. P. -158 C. at 11 mm. pressure), piperidinopropanoland m-dimethylor methyl-ethyl-amino-cyclohexanol.

Furthermore, methyl-ethylaminoethanol or -propanol,ethyl-propylaminoethano1 or -propan- 01 as well asmethylpropylaminoethanol or -propanel may also be used.

Ezrample 2 19 parts of di-isobutyl acetic acid are heated to boiling for24 hours under stirring with 14 parts of c-chloroethyl diethylamine andwith 20 parts of potassium carbonate in 250 parts by volume of dryacetic acid ester. After cooling the potassium chloride is filtered bysuction, the residue is washed with acetic acid ester and the combinedfiltrates are extracted by means of dilute hydrochloric acid. The acidsolution thus obtained is extracted with ether, then the base is madefree by addition of a potassium carbonate solution and extracted withether. After having dried the ethereal solution the solvent is distilledoil. The residue boils at a pressure of 0.8 mm. at 98-99 C.

In the same manner for instance the n-butyl isobutyl acetic acid andn-amyl isobutyl acetic acid may also be converted into the correspondingbasic esters.

Example 3 35 parts of di-isobutyl acetic acid chloride or the equivalentquantity of the bromide are caused to react with 17 parts of ethylenechlorohydrine in the presence of pyridine. teraction the reactionmixture is extracted with ether and water, the ethereal solution isdried and the solvent distilled off. The residue is fractionated invacuo and 20 parts of the so-obtained diisobutyl aceticacid-c-chloroethyl ester are allowed to react in the heat with 14 partsof piperi-1 dine. The mixture is extracted with ether and water. Afterhaving dried the ethereal solution the solvent is distilled off. Theresidue boils at 0.5 mm. pressure at 115-l1'7 C. The same substance maybe obtained by condensation of di isobutyl acetic acid chloride withpiperidinoethanol.

Example 4 9.5 parts of cli-isobutyl acetic acid chloride areadded, whilestirring, to 5.2 parts of'dimethyl amino propanol and this mixture isheated for a short time to 166 C. The reaction product is worked up inthe same manner as described in EX- ample 1, whereby the dimethylaminopropanol ester of the di-isobutyl acetic acid is obtained which boils ata pressure of 12 mm. at l37-139 C.

' What we claim is:

l. A basic ester of a monoalkyl-isobuty1 acetic acid of the formulacn-cnf-o-oooA-x CH3 (lower alkyl) wherein A represents a member of thegroup consisting of an unsubstituted alkylene chain con taining from twoto threecarbon atoms and of a cyclohexane ring and X represents a memberof the group consisting of the radicals OKs-CH2 v -N=(lower alk'ylh andN CH2 V CHz-GHz which compound is soluble in organic solvents andinsoluble in water, forming with acids watersoluble salts ofantispasmodic properties.

. 2.'A basic ester of a di-isobutyl acetic acid of the formula wherein Arepresents a member of the group consisting of an unsubstituted alkylenechain 1 GET-CHI CH2 GET-CH2 which compound is soluble in organicsolvents -N=(lower alkylla and -N After complete in- 1 containing fromtwo to in water boiling at 11 mm. pressure CH3 lower alkyl CH--CHz-CHC O0 .AN CH3 (lower alkyl) lower alkyl wherein A represents a member or thegroup consisting of an unsubstituted alkylene chain three carbon atomsand of a cyclohexane ring, which compound is soluble in organic solventsand insoluble in water, forming with acids water-soluble salts ofantispasmodic properties.

4. The basic ester of di-isobutyl acetic acid of the formula CHr-CH:

being soluble in organic solvents and insoluble in water, and boiling at0.5 mm. pressure at l15-l1'1 C. and forming with acids water-solublesalts of antispasmodic properties.

5. The basic ester of di-isobutyl acetic acid of the formula CH2 v a/CHCH2 =CH.COOCHz.CHr-N CzHe CHa.CHz.CH2

CH3- I onoooonaomonm CHI-CH2 C2H5 solvents and insoluble at 148-150 C.and forming with acids water-soluble salts of antispasmodic properties.

being soluble in organic HENRY MARTIN. ALFRED MARGOT.

REFERENCES CITED The following references are of record in the file ofthis patent: V

UNITED STATES PATENTS Name Date Bohm et a1 Nov. 26, 1940 Number

